Processes for the preparation of sitagliptin and pharmaceutically acceptable salts thereof

ABSTRACT

There is provided a process for preparation of sitagliptin of Formula II or a pharmaceutically acceptable salt thereof by deprotection of Formula IX.

This application is a Continuation Application of U.S. patentapplication Ser. No. 13/648,026, filed on Oct. 9, 2012, which is aDivisional of U.S. patent application Ser. No. 12/809,200 filed Jun. 18,2010, which claims the benefit of International Application No.PCT/US2008/087491 filed Dec. 18, 2008; Indian Application No.3076/CHE/2007, filed Dec. 20, 2007; Indian Application No. 159/CHE/2008filed Jan. 18, 2008; Indian Application No. 1188/CHE/2008 filed May 14,2008; U.S. Application No. 61/058,764 filed Jun. 4, 2008; U.S.Application No. 61/058,975 filed Jun. 5, 2008 and U.S. Application No.61/097,910 filed Sep. 18, 2008, all of which are hereby incorporateherein by reference in their entireties.

INTRODUCTION

The present application relates to sitagliptin, its salts, and itspolymorphs, and processes for the preparation of sitagliptin, its salts,and its polymorphs.

Sitagliptin is(R)-7-(1-oxo-3((R)-amino)-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinerepresented by the structural Formula II.

Sitagliptin is an orally-active dipeptidyl peptidase-4 (DPP-IV) enzymeinhibitor that improves glycemic control in patients with Type 2diabetes mellitus by slowing the inactivation of incretin hormones.Sitagliptin may be used as a monotherapy, as an adjunct to diet andexercise, or in combination with metformin or a PPARγ agonist (e.g.,thiazolidinediones).

U.S. Pat. No. 6,699,871 describes a class ofbeta-amino-tetrahydrotriazolo[4,3-a]pyrazines that are potent inhibitorsof DPP-IV and therefore useful for the treatment of Type 2 diabetes.Specifically disclosed in U.S. Pat. No. 6,699,871 is sitagliptin.Pharmaceutically acceptable salts of this compound are genericallyencompassed within the scope of U.S. Pat. No. 6,699,871. It alsodiscloses a process for the preparation of sitagliptin and relatedcompounds.

International Application Publication No. WO 2004/085661 discloses aprocess for the preparation of sitagliptin in which S-phenyl glycineamide is used as a chiral auxilary to form an intermediate thatsubsequently provides the required enantiomer sitagliptin).

International Application Publication No. WO 2004/087650 disclosesanother process in which N-protected3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyric acid is synthesizedenantio-selectively, condensed with a pyrazine intermediate, anddeprotected to provide sitagliptin.

U.S. Pat. No. 7,326,708 discloses the dihydrogen phosphate salt ofsitagliptin and processes for the preparation thereof.

International Application Publication No. WO 2004/085378 discloses aprocess for the preparation of sitagliptin, wherein the reduction of thesitagliptin intermediate is carried out by using rhodium metal and achiral ferrocenyl diphosphine.

Although several processes have been reported in the prior art for thepreparation of sitagliptin, they suffer from one or more drawbacks suchas involving the use of hazardous regents, like platinum oxide, rhodiumcatalyst, etc., costly reagents, such as chloro pyrazine,dichloropyrazine, etc., and extensive protection and deprotection steps.Hence, there is an ongoing need for simple, cost effective, andindustrially viable processes for the production of sitagliptin and itspharmaceutically acceptable salts.

Crystalline salts of sitagliptin are known. International ApplicationPublication No. WO 2005/072530 describes various crystalline salts ofsitagliptin, International Application Publication No. WO 2006/033848describes amorphous form of the dihydrogen phosphate salt ofsitagliptin. International Application Publication No. WO 2005/020920discloses two crystalline anhydrous forms of the dihydrogen phosphatesalt of sitagliptin namely Form I and Form III, and a crystallinedesolvated anhydrate Form II. International Application Publication No.WO 2005/030127 discloses a crystalline anhydrate Form IV of thedihydrogen phosphate salt of sitagliptin. International ApplicationPublication No. WO 2005/072530 discloses crystalline hydrochloric acid,benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid,and tartaric acid salts of sitagliptin. International ApplicationPublication No. WO 2007/035198 discloses dodecylsulfate salt ofsitagliptin.

There remains a need for further improvement in properties of solidsitagliptin, such as stability, purity, flowability, vaporimpermeability, solubility, and bioavailability.

SUMMARY OF THE APPLICATION

The present invention includes processes for the preparation ofsitagliptin, which processes comprise at least one of the steps of:

(i) reacting7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinewith a first reagent to afford7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine;

(ii) converting the7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinewith a second reagent to7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine;

(iii) treating the7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinewith a third reagent to afford a diastereomeric salt of7-(1-oxo-3((R)-amino)-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine;

(iv) isolating the diastereomeric salt;

(v) treating the diastereomeric salt with an acid or a base to affordsitagliptin freebase; and

(vi) optionally treating the sitagliptin freebase with an acid to affordan acid addition salt of sitagliptin.

The present invention includes processes for the preparation ofsitagliptin, which processes comprise at least one of the steps of:

(i) reacting7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinewith a chiral reagent to produce the compound of the Formula VIII,wherein R is an C₁-C₄ alkyl;

(ii) converting the compound of Formula VIII to the compound of FormulaIX, wherein wherein R is as defined above;

(iii) converting the compound of Formula VIII using an acid or base or acatalyst to afford sitagliptin freebase

(iv) optionally treating the sitagliptin freebase with an acid to affordan acid addition salt of sitagliptin.

The present invention includes anhydrous crystalline sitagliptindihydrogen phosphate of Formula I′ (also referred to hereinafter as FormA).

Form A may be characterized by differential scanning calorimetry (DSC)thermogram with onset at about 201° C. and endotherm peak at about205.5° C.

Form A may also be characterized by its X-ray diffraction pattern withcharacteristic peaks at diffraction angles 2-theta of about 4.58, 9.23,12.24, 13.88, 18.23, 23.63, 24.24, and 26.68±0.2 degrees.

Form A may also be characterized by X-ray diffraction patternsubstantially as shown in FIG. 1.

Also, Form A may be characterized by thermo gravimetric analysis (TGA)curve corresponding to a weight loss of about 0.038% (0.01082 mg) up toa temperature of about 100° C. (as shown in FIG. 3).

The present invention includes processes for the preparation of Form A,which processes comprise the step of treating sitagliptin freebase withphosphoric acid in aqueous isopropanol having a water content of lessthan about 6%.

In addition to Form A, the present invention includes the sulfuric acid,hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid,oxalic acid, succinic acid, mandelic acid, fumaric acid, and lactic acidsalts of sitagliptin.

The present invention includes processes for the preparation of salts ofsitagliptin, which processes comprise at least one of the steps of:

(a) providing a solution of a salt of sitagliptin in a solvent;

(b) isolating the salt of sitagliptin from the solution of Step (a); and

(c) recovering the crystalline salt of sitagliptin and optionally dryingit.

There present invention includes pharmaceutical compositions comprisingsitagliptin according to the present invention together with at leastone pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is an illustration of X-ray powder diffraction (XRPD) pattern ofcrystalline anhydrate Form A of the dihydrogen phosphate salt ofsitagliptin.

FIG. 2 is an illustration of differential scanning calorimetry (“DSC”)curve of crystalline anhydrate Form A of the dihydrogen phosphate saltof sitagliptin.

FIG. 3 is an illustration of thermogravimetric analysis (TGA) curve ofcrystalline anhydrate Form A of the dihydrogen phosphate salt ofsitagliptin.

FIG. 4 is an illustration of powder X-ray diffraction (“PXRD”) patternof crystalline sitagliptin sulfate prepared according to example 14.

FIG. 5 is an illustration of differential scanning calorimetry (“DSC”)curve of crystalline sitagliptin sulfate prepared according to example14.

FIG. 6 is an illustration of thermogravimetric analysis (“TGA”) curve ofcrystalline sitagliptin sulfate prepared according to example 14.

FIG. 7 is an illustration of PXRD pattern of crystalline sitagliptinhydrobromide prepared according to example 15.

FIG. 8 is an illustration of DSC curve of crystalline sitagliptinhydrobromide prepared according to example 15.

FIG. 9 is an illustration of TGA curve of crystalline sitagliptinhydrobromide prepared according to example 15.

FIG. 10 is an illustration of PXRD pattern of crystalline sitagliptinmethane sulfonate prepared according to example 16.

FIG. 11 is an illustration of DSC curve of crystalline sitagliptinmethane sulfonate prepared according to example 16.

FIG. 12 is an illustration of TGA curve of crystalline sitagliptinmethane sulfonate prepared according to example 16.

FIG. 13 is an illustration of PXRD pattern of crystalline sitagliptinacetate prepared according to example 17.

FIG. 14 is an illustration of DSC curve of crystalline sitagliptinacetate prepared according to example 17.

FIG. 15 is an illustration of TGA curve of crystalline sitagliptinacetate prepared according to example 17.

FIG. 16 is an illustration of PXRD pattern of crystalline sitagliptinbenzoate prepared according to example 18.

FIG. 17 is an illustration of DSC curve of crystalline sitagliptinbenzoate prepared according to example 18.

FIG. 18 is an illustration of TGA curve of crystalline sitagliptinbenzoate prepared according to example 18.

FIG. 19 is an illustration of PXRD pattern of crystalline sitagliptinoxalate prepared according to example 19.

FIG. 20 is an illustration of DSC curve of crystalline sitagliptinoxalate prepared according to example 19.

FIG. 21 is an illustration of TGA curve of crystalline sitagliptinoxalate prepared according to example 19.

FIG. 22 is an illustration of PXRD pattern of crystalline sitagliptinsuccinate prepared according to example 20.

FIG. 23 is an illustration of DSC curve of crystalline sitagliptinsuccinate prepared according to example 20.

FIG. 24 is an illustration of TGA curve of crystalline sitagliptinsuccinate prepared according to example 20.

FIG. 25 is an illustration of PXRD pattern of crystalline sitagliptinmendelate prepared according to example 21.

FIG. 26 is an illustration of DSC curve of crystalline sitagliptinmendelate prepared according to example 21.

FIG. 27 is an illustration of TGA curve of crystalline sitagliptinmendelate prepared according to example 21.

FIG. 28 is an illustration of PXRD pattern of crystalline sitagliptinfumarate prepared according to example 22.

FIG. 29 is an illustration of DSC curve of crystalline sitagliptinfumarate prepared according to example 22.

FIG. 30 is an illustration of TGA curve of crystalline sitagliptinfumarate prepared according to example 22.

FIG. 31 is an illustration of PXRD pattern of crystalline sitagliptinlactate prepared according to example 23.

FIG. 32 is an illustration of DSC curve of crystalline sitagliptinlactate prepared according to example 23.

FIG. 33 is an illustration of TGA curve of crystalline sitagliptinlactate prepared according to example 23.

DETAILED DESCRIPTION

All percentages and ratios used herein are by weight of the totalcomposition and all measurements made are at 25° C. and normal pressureunless otherwise designated. All temperatures are in Degrees Celsiusunless specified otherwise. The present invention can comprise (openended) of the components of the present invention as well as otheringredients or elements described herein.

As used herein, “comprising” means the elements recited, or theirequivalent in structure or function, plus any other element or elementswhich are not recited. The terms “having” and “including” are also to beconstrued as open ended unless the context suggests otherwise.

All ranges recited herein include the endpoints, including those thatrecite a range “between” two values.

Terms such as “about,” “generally,” “substantially,” and the like are tobe construed as modifying a term or value such that it is not anabsolute, but does not read on the prior art. Such terms will be definedby the circumstances and the terms that they modify as those terms areunderstood by those of skill in the art. This includes, at very least,the degree of expected experimental error, technique error andinstrument error for a given technique used to measure a value.

This document may refer to a material, such as in this instance, saltsof sitagliptin, and its crystalline forms, solvates, or optical isomersby reference to patterns, spectra, or other graphical data,“substantially” as shown in a Figure, or by one or more data points. By“substantially” used in such a context, it will be appreciated thatpatterns, spectra, and other graphical data can be shifted in theirpositions, relative intensities, and/or values due to a number offactors known to those of skill in the art. For example, in thecrystallographic and powder X-ray diffraction arts, such shifts in peakpositions or the relative intensities of one or more peaks can occurbecause of, without limitation: the equipment used, the samplepreparation protocol, preferred packing and orientations, the radiationsource, operator error, method and length of data collection, and thelike. However, those of ordinary skill in the art should be able tocompare the figures herein with a pattern generated of an unknown formof, in this case, salts of sitagliptin, and confirm its identity as oneof the forms disclosed and claimed herein. The same holds true for othertechniques which may be reported herein.

In addition, where a reference is made to a figure, it is permissibleto, and this document includes and contemplates, the selection of anynumber of data points illustrated in the figure that uniquely definethat crystalline form, salt, or optical isomer.

When a molecule or other material is identified herein as “pure”, itgenerally means, unless specified otherwise, that the material is 99%pure or more, as determined by methods conventional in art such as highperformance liquid chromatography (HPLC) or optical methods. In general,this refers to purity with regard to unwanted residual solvents,reaction byproducts, impurities and unreacted starting materials. In thecase of stereoisomers, “pure” also means 99% of one enantiomer ordiastereomer, as appropriate. “Substantially pure” refers to the same as“pure except that the lower limit is about 98% pure or more andlikewise, “essentially pure” means the same as “pure” except that thelower limit is about 95% pure.

As used herein, the terms “salt(s) of sitagliptin,” “sitagliptinsalt(s)” and other similar phrases encompass crystalline and amorphousforms, solvates, hydrates, stereoisomers, both individual and inmixtures thereof, racemates, enantiomers, and the like

The present invention includes processes for the preparation ofsitagliptin, which processes comprise at least one of the steps of:

(i) reacting7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazineof Formula VI

with a reagent, optionally in the presence of a solvent, to afford7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazineof Formula V;

(ii) converting the compound of Formula V to7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazineof Formula IV;

(iii) treating the compound of Formula IV with a reagent to afford adiasteromeric salt of sitagliptin of Formula III;

wherein X is the reagent used for the preparation of said diasteromericsalt;

(iv) isolating the diasteromeric salt of sitagliptin;

(v) treating the diasteromeric salt of sitagliptin with an acid or abase to afford sitagliptin freebase of Formula II;

(vi) optionally treating the sitagliptin freebase with an acid to affordan acid addition salt of sitagliptin of Formula I

wherein Y is an acid residue.

Step (i) involves reacting the compound of Formula VI with a reagent,optionally in a solvent, to afford the compound of the formula (V)

Suitable reagents include and are not limited to ammonia sources, suchas, for example, ammonium chloride, ammonium bromide, ammonium iodide,ammonium carbonate, ammonium formate, ammonium acetate, formamide,ammonium formate in combination with methanolic ammonia or ethanolicammonia, ammonium formate in combination with isopropanol ammonia,ammonium formate in combination with aqueous ammonia, ammonium formatein combination with formic acid, formamide in combination with formicacid, formamide in combination with formic acid and isopropanol ammonia,formamide in combination with formic acid and methanolic ammonia,formamide in combination with formic acid and aqueous ammonia, or amixture thereof. For example, the ammonia source may be ammonium acetatein combination with aqueous ammonia.

Suitable solvents that may be used include and are not limited to,alcohols, such as, for example methanol, ethanol, isopropanol,n-butanol, and the like; nitriles like acetonitrile, propionitrile, andthe like; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, n-butanone, and the like; halogenatedsolvents, such as, for example, dichloromethane, ethylene dichloride,chloroform, and the like; esters, such as, for example ethyl acetate,n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents,such as, for example, toluene, xylene, n-hexane, n-heptane, cyclohexane,and the like; ethers, such as, for example, 1,4-dioxane,tetrahydrofuran, and the like; aprotic polar solvents, such as, forexample, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),dimethylacetamide (DMA); water; or mixtures thereof.

A suitable temperature for the reaction of Step (i) may be less thanabout 150° C., or less than about 120° C., or less than about 80° C., orless than about 60° C., or any other suitable temperatures.

Step (ii) involves conversion of the compound of the Formula V to acompound of Formula IV.

Suitable reagents that may be used for the conversion include and arenot limited to sodium borohydride, lithium aluminium hydride, vitride,sodium cyano borohydride, palladium-carbon, RANEY nickel, and platiniumoxide, or any other suitable reagent. For example, the reagent may besodium cyano borohydride.

Suitable solvents that may be used include and are not limited to,alcohols, such as, for example methanol, ethanol, isopropanol,n-butanol, and the like; nitriles like acetonitrile, propionitrile, andthe like; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, n-butanone, and the like; halogenatedsolvents, such as, for example, dichloromethane, ethylene dichloride,chloroform, and the like; esters, such as, for example ethyl acetate,n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents,such as, for example, toluene, xylene, n-hexane, n-heptane, cyclohexane,and the like; ethers, such as, for example, 1,4-dioxane,tetrahydrofuran, and the like; aprotic polar solvents, such as, forexample, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),dimethylacetamide (DMA); water; or mixtures thereof.

A suitable temperature for the reaction of Step (ii) may be less thanabout 250° C., or less than about 200° C., or less than about 150° C.,or less than about 100° C., or less than about 80° C., or less thanabout 60° C., or any other suitable temperature.

The reaction may be carried out for any desired time period ranging fromabout 30 minutes to about 10 hours or longer.

Step (iii) involves treating the compound of Formula IV with a reagentto afford a diasteromeric salt of sitagliptin of Formula III

Suitable reagents that may be used include and are not limited to:S-(+)-mandelic acid, R-(−)-mandelic acid, (1S)-(+)-camphor-10-sulfonicacid, (1R)-(−)-camphor-10-sulfonic acid, L-malic acid, D-malic acid,L-maleic acid, D-maleic acid, (−)-naproxen, (+)-naproxen, (−)-ibuprofen,(+)-ibuprofen, (1R)-(+)-3-bromocamphor-10-sulfonic acid,(1S)-(−)-3-bromocamphor-10-sulfonic acid, L-(+)-tartaric acid,D-(−)-tartaric acid, (+)-dibenzoyl-D-tartaric acid,(−)-dibenzoyl-L-tartaric acid, (+)-dipara-tolyl-D-tartaric acid,(−)-dipara-tolyl-L-tartaric acid, L-(−)-pyroglutamic acid,L-(+)-pyroglutamic acid, (−)-lactic acid, L(+)-lactic acid, L-lysine,D-lysine, and mixtures of thereof. For example, the reagent may be(−)-di-para-tolyl-L-tartaric acid

Suitable solvents that may be used include and are not limited to,alcohols, such as, for example methanol, ethanol, isopropanol,n-butanol, and the like; nitriles like acetonitrile, propionitrile, andthe like; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, n-butanone, and the like; halogenatedsolvents, such as, for example, dichloromethane, ethylene dichloride,chloroform, and the like; esters, such as, for example ethyl acetate,n-propyl acetate, isopropyl acetate, and the like; hydrocarbon solvents,such as, for example, toluene, xylene, n-hexane, n-heptane, cyclohexane,and the like; ethers, such as, for example, 1,4-dioxane,tetrahydrofuran, and the like; aprotic polar solvents, such as, forexample, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),dimethylacetamide (DMA); water; or mixtures thereof.

A suitable temperature for the reaction of Step (iii) may be less thanabout 150° C., or less than about 120° C., or less than about 80° C., orless than about 60° C., or any other suitable temperatures.

The reaction may be carried out for any desired time periods rangingfrom about 30 minutes to about 30 hours or longer.

Step (iv) involves isolating the diasteromeric salt of sitagliptin ofFormula III

The diastereomeric salt formed in Step (iii) may be recovered byconventional methods including decantation, centrifugation, gravityfiltration, suction filtration, or other techniques known in the art forthe recovery of solids. The recovered solid may be further dried. Dryingmay be suitably carried out using a tray dryer, vacuum oven, air oven,fluidized bed drier, spin flash dryer, flash dryer, and the like atatmospheric pressure or under reduced pressure. Drying may be carriedout at a temperature of less than about 150° C., or less than 120° C.,or less than 100° C., or less than about 60° C., or less than about 40°C., or any other suitable temperature, at atmospheric pressure or underreduced pressure, and in the presence or absence of an inert atmospheresuch as nitrogen, argon, neon, or helium. The drying may be carried outfor any desired time period to achieve the desired quality of theproduct, such as, for example, about 1 to about 15 hours or longer.

The diasteromeric salt of Formula III may be purified by processes knownin the art. For example, the diasteromeric salt of Formula III may bepurified by precipitation or making a slurry in a suitable solvent.Precipitation may be achieved by methods such as crystallization, addingan anti-solvent to a concentrated solution of the said diastereomericsalt, or any other suitable method known in the art.

Step (v) involves treating the diasteromeric salt of Formula III with anacid or a base to afford sitagliptin freebase of Formula II.

Suitable bases that may be used for treating the diasteromeric salt ofFormula II include and are not limited to: inorganic bases, such as, forexample, sodium hydroxide, potassium hydroxide, sodium methoxide,potassium teritarybutoxide, sodium teritarybutoxide, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, and thelike, either alone or as their aqueous solutions; organic bases, suchas, for example, triethylamine, pyridine, N-methyl Morpholine,diisopropyl amine, diisopropyl ethylamine, and the like; resins, suchas, for example, ion exchange resins; and mixtures thereof.

Suitable acids that may be used for treating the diasteromeric salt ofFormula II include and are not limited to: inorganic acids, such as, forexample, hydrochloric acid, nitric acid, sulphuric acid, phosphoricacid, and the like; organic acids, such as, for example, acetic acid,propionic acid, butyric acid, and the like; and mixtures thereof.

Suitable solvents that may be used in Step (v) include and are notlimited to: alcohols, such as, for example, ketones, such as, forexample, methyl isobutyl ketone, methyl ethyl ketone, n-butanone, andthe like; halogenated solvents, such as, for example, dichloromethane,ethylene dichloride, chloroform, and the like; esters, such as, forexample, ethyl acetate, n-propyl acetate, isopropyl acetate, and thelike; hydrocarbon solvents, such as, for example, toluene, xylene,cyclohexane, and the like; ethers, such as, for example, 1,4-dioxane,tetrahydrofuran, and the like; and mixtures thereof.

A suitable temperature for Step (v) may be less than about 150° C., orless than about 120° C., or less than about 80° C., or less than about60° C., or any other suitable temperatures.

A suitable time for the reaction of Step (v) may be from about 30minutes to about 20 hours or longer to achieve the desired yield andquality.

Step (vi) involves optionally treating sitagliptin freebase with an acidto afford an acid addition salt of sitagliptin of Formula I

Suitable acids for Step (vi) include and are not limited to phosphoricacid, hydrochloric acid, oxalic acid, hydrobromic acid, acetic acid,formic acid, citric acid, and the like.

Conversion of the acid addition salt of sitagliptin of Formula I intositagliptin freebase is also contemplated.

For example, sitagliptin free base may be treated with phosphoric acidto afford sitagliptin phosphate of Formula (I′). For the reaction, themolar equivalents of phosphoric acid that may be used may range fromabout 0.5 to about 2.0 molar equivalents with respect to sitagliptinfree base.

The acid addition salt of sitagliptin of Formula I obtained in Step (vi)may be dried. Drying may be carried out in a tray dryer, vacuum oven,air oven, fluidized bed drier, spin flash dryer, flash dryer and thelike, at atmospheric pressure or under reduced pressure.

The drying may be carried out at temperatures of less than about 100°C., or less than about 90° C., or less than about 60° C., or less thanabout 50° C., or any other suitable temperature at atmospheric pressureor under reduced pressure. The drying may be carried out for any desiredtime ranging from about 1 to 20 hours or longer.

Optionally, the salt of sitagliptin may be purified by processes knownin the art. For example, the salt of sitagliptin may be purified byprecipitation or making a slurry in a suitable solvent. Theprecipitation may be achieved by crystallization, by adding ananti-solvent, or any other suitable method known in the art.

The present invention includes stereoselective processes for thepreparation of sitagliptin, which processes comprise at least one of thesteps of:

(i) reacting7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazineof Formula VI:

with a chiral reagent of Formula VII:

wherein R is C₁-C₄ alkyl, to produce the compound of the Formula VIII;

(ii) converting the compound of Formula VIII to the compound of FormulaIX

(iii) converting the compound of Formula VIII using an acid or base or acatalyst to afford sitagliptin freebase of Formula II; and

(iv) optionally treating the sitagliptin freebase with an acid to affordan acid addition salt of sitagliptin of Formula I

wherein Y is an acid residue.

Step (i) involves reacting the compound of the formula VI with a chiralcompound of Formula VII to produce a chiral enamine of Formula VIII.

For example, the chiral reagent may be (R)-1-phenylethylamine.

For the reaction of Step (i), the molar equivalents of the chiralcompound of Formula VII may range from about 1.0 to about 2.0 molarequivalents with respect to the compound of Formula VI.

The reaction of Step (i) may be conducted in a solvent. Solvents thatmay be used include and not limited to: alcohols, such as, for example,methanol, ethanol, isopropanol, and n-butanol; organic acids, such as,for example, acetic acid and propionic acid; ketones, such as, forexample, acetone, methyl isobutyl ketone, methyl ethyl ketone, andn-butanone; halogenated solvents, such as, for example, dichloromethane,ethylene dichloride, and chloroform; esters, such as, for example, ethylacetate, n-propyl acetate, and isopropyl acetate; hydrocarbon solvents,such as, for example, toluene, xylene, n-hexane, n-heptane, andcyclohexane; ethers, such as, for example, 1,4-dioxane, andtetrahydrofuran; organic acids, such as, for example, acetic acid,propionic acid, and the like; and mixtures thereof.

A suitable temperature for the reaction of Step (i) may be less thanabout 150° C., or less than about 120° C., or less than about 80° C., orless than about 60° C., or any other suitable temperatures.

A suitable time for the reaction of Step (i) may be from about 30minutes to about 10 hours or longer.

Step (ii) involves converting the compound of Formula VIII to a compoundof Formula IX.

The conversion may be achieved by methods including and not limited toreduction. A reduction may be carried out in the presence of a catalyst,such as, for example, platinum oxide (PtO₂). The molar equivalents ofreduction catalyst may range from about 0.05 to about 1.0 molarequivalent with respect to the compound of Formula VIII.

Solvents that may be used as in Step (ii) include and are not limited toalcohols, such as, for example, methanol, ethanol, isopropanol, andn-butanol; organic acids, such as, for example, acetic acid andpropionic acid; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, and n-butanone; halogenated solvents, suchas, for example, dichloromethane, ethylene dichloride, and chloroform;esters, such as, for example, ethyl acetate, n-propyl acetate, andisopropyl acetate; hydrocarbon solvents, such as, for example, toluene,xylene, n-hexane, n-heptane, and cyclohexane; ethers, such as, forexample, 1,4-dioxane and tetrahydrofuran; aprotic polar solvents, suchas, for example, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),and dimethylacetamide (DMA); or mixtures thereof.

A suitable temperature for the reaction of Step (ii) may be less thanabout 200° C., or less than about 150° C., or less than about 100° C.,or less than about 60° C., or any other suitable temperatures.

A suitable time for the reaction of Step (ii) may be from about 30minutes to about 10 hours or longer.

Step (iii) involves converting the compound of Formula IX using an acidor base or a catalyst to afford sitagliptin freebase of Formula II.

The conversion of Step (iii) may be achieved by techniques known in theart. For example, the conversion of Step (iii) may be achieved byhydrogenation in the presence of a catalyst, such as, for example,palladium on carbon, nickel on carbon, and palladium hydroxide oncarbon.

Solvents that may be used as in Step (iii) include and are not limitedto alcohols, such as, for example, methanol, ethanol, isopropanol, andn-butanol; organic acids, such as, for example, acetic acid andpropionic acid; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, and n-butanone; halogenated solvents, suchas, for example, dichloromethane, ethylene dichloride, and chloroform;esters, such as, for example, ethyl acetate, n-propyl acetate, andisopropyl acetate; hydrocarbon solvents, such as, for example, toluene,xylene, n-hexane, n-heptane, and cyclohexane; ethers, such as, forexample, 1,4-dioxane and tetrahydrofuran; aprotic polar solvents, suchas, for example, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),and dimethylacetamide (DMA); or mixtures thereof.

A suitable temperature for the reaction of Step (ii) may be less thanabout 200° C., or less than about 150° C., or less than about 100° C.,or less than about 60° C., or any other suitable temperatures.

A suitable time for the reaction of Step (ii) may be from about 30minutes to about 10 hours or longer.

Step (iv) involves optionally treating the sitagliptin freebase ofFormula II with an acid to afford an acid addition salt of sitagliptinof Formula I.

Suitable acids for Step (iv) include and are not limited to phosphoricacid, hydrochloric acid, oxalic acid, hydrobromic acid, acetic acid,formic acid, citric acid, and the like.

Conversion of the acid addition salt of sitagliptin of Formula I intositagliptin freebase is also contemplated.

For example, sitagliptin free base may be treated with phosphoric acidto afford sitagliptin phosphate of Formula I′. For the reaction, themolar equivalents of phosphoric acid that may be used may range fromabout 0.5 to about 2.0 molar equivalents with respect to sitagliptinfree base.

The acid addition salt of sitagliptin of Formula I obtained in Step (vi)may be dried. Drying may be carried out in a tray dryer, vacuum oven,air oven, fluidized bed drier, spin flash dryer, flash dryer and thelike, at atmospheric pressure or under reduced pressure. The drying maybe carried out at temperatures of less than about 100° C., or less thanabout 90° C., or less than about 60° C., or less than about 50° C., orany other suitable temperature at atmospheric pressure or under reducedpressure. The drying may be carried out for any desired time rangingfrom about 1 to 20 hours or longer.

Optionally, the salt of sitagliptin may be purified by processes knownin the art. For example, the salt of sitagliptin may be purified byprecipitation or making a slurry in a suitable solvent. Theprecipitation may be achieved by crystallization, by adding ananti-solvent, or any other suitable method known in the art.

Sitagliptin freebase and the pharmaceutically acceptable salts thereofprepared in accordance with the processes described in the presentapplication are substantially free of process or structure relatedimpurities, meaning the sitagliptin freebase or pharmaceuticallyacceptable salt thereof comprises less than about 0.5%, or less thanabout 0.3%, or less than about 0.2%, or less than about 0.1%, or lessthan about 0.05% by weight of its corresponding process or structuralrelated impurities.

The present invention includes processes for the preparation of acompound of Formula VI, which processes comprise at least one of thesteps of:

(i) reacting 2,4,5-trifluorophenylacetic acid of Formula XIII with2,2-dimethyl-1,3-dioxane-4,6-dione (meldrums acid) of Formula XII

in the presence of 1,1-carbonyl diimidazole to afford5-(1-hydroxy-2-(2,4,5-trifluorophenyl)-ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dioneof Formula XI;

and

(ii) reacting the compound of Formula XI with3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinehydrochloride of Formula X

in the presence of diisopropylethylamine to afford compound of FormulaVI.

Step (i) involves condensation of 2,4,5-trifluorophenylacetic acid ofFormula XIII with 2,2-dimethyl-1,3-dioxane-4,6-dione (meldrums acid) ofFormula XII.

The molar equivalents of meldrums acid that may be used in Step (i) maybe less than about 2.0, or less than about 3.0, or less than about 5.0molar equivalents with respect to the compound of Formula XIII.

Bases that may be used in Step (i) include and are not limited to:organic bases, such as, for example, triethyl amine, diisopropylethylamine, pyridine, imidazole, N-methyl morpholine, sodium methoxide,diisopropyl amine, 1,1-carbonyl diimidazole, and the like, inorganicbases, such as, for example, sodium carbonate, potassium carbonate,sodium bicarbonate, and potassium bicarbonate; or mixtures thereof.

Organic solvents that may be used in Step (i) include and are notlimited to: alcohols, such as, for example, methanol, ethanol,isopropanol, n-butanol, and the like; organic acids, such as, forexample, acetic acid, propionic acid, and the like; ketones, such as,for example, acetone, methyl isobutyl ketone, methyl ethyl ketone,n-butanone, and the like; halogenated solvents, such as, for example,dichloromethane, ethylene dichloride, chloroform, and the like; esters,such as, for example, ethyl acetate, n-propyl acetate, isopropylacetate, and the like; hydrocarbon solvents, such as, for example,toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; ethers,such as, for example, 1,4-dioxane, tetrahydrofuran, and the like;aprotic polar solvents, such as, for example, N,N-dimethylformamide(DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); water; andmixtures thereof.

A suitable temperature for the reaction of Step (ii) may be less thanabout 120° C., or less than about 100° C., or less than about 60° C., orany other suitable temperatures.

A suitable time for the reaction of Step (ii) may be from about 30minutes to about 10 hours or longer.

Step (ii) involves preparation of the compound of Formula VI by reactingcompound of Formula XI with3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazinehydrochloride of Formula X in the presence of diisopropylethylamine inan organic solvent to afford compound of Formula VI.

3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazinehydrochloride of Formula X may be prepared, e.g., by the process ofReference Example 1 herein or as disclosed in U.S. Pat. No. 7,326,708,which patent is incorporated herein by reference in its entirety.

The molar equivalents of3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazinehydrochloride of Formula X may be less than about 3.0, or less thanabout 2.0, or less than about 1.0 molar equivalents with respect to thecompound of Formula XI.

The molar equivalents of diisopropylethylamine may be less than about3.0, or less than about 2.0, or less than about 1.0 molar equivalentswith respect to the compound of Formula XI.

Solvents that may be used as in Step (iii) include and are not limitedto alcohols, such as, for example, methanol, ethanol, isopropanol, andn-butanol; organic acids, such as, for example, acetic acid andpropionic acid; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, and n-butanone; halogenated solvents, suchas, for example, dichloromethane, ethylene dichloride, and chloroform;esters, such as, for example, ethyl acetate, n-propyl acetate, andisopropyl acetate; hydrocarbon solvents, such as, for example, toluene,xylene, n-hexane, n-heptane, and cyclohexane; ethers, such as, forexample, 1,4-dioxane and tetrahydrofuran; aprotic polar solvents, suchas, for example, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),and dimethylacetamide (DMA); or mixtures thereof.

A suitable temperature for the reaction of Step (ii) may be less thanabout 120° C., or less than about 80° C., or less than about 60° C., orany other suitable temperatures.

A suitable time for the reaction of Step (ii) may be from about 30minutes to about 10 hours or longer.

The processes of the present invention may be used to make anhydrouscrystalline sitagliptin dihydrogen phosphate of Formula I′ (alsoreferred to hereinafter as Form A).

Form A may be characterized by differential scanning calorimetry (DSC)thermogram with onset at about 201° C. and endotherm peak at about205.5° C.

Form A may also be characterized by its XPRD characteristic peaks atdiffraction angles 2-theta of about 4.58, 9.23, 12.24, 13.88, 18.23,23.63, 24.24, and 26.68±0.2 degrees.

Form A may also be characterized by the X-ray diffraction patternsubstantially as shown in FIG. 1.

Also, Form A may be characterized by thermo gravimetric analysis (TGA)curve corresponding to a weight loss of about 0.038% (0.01082 mg) up toa temperature of about 100° C. (as shown in FIG. 3).

The present invention also includes processes for the preparation ofForm A, which processes comprise the step of treating sitagliptinfreebase with phosphoric acid in a solvent having a water content ofless than about 6%.

The molar equivalents of phosphoric acid may be less than about 2.0, orless than about 1.0, or less than about 0.5 molar equivalents withrespect to sitagliptin free base. The solvent may be aqueous isopropanolwith a concentration of water within the solvent of less than about 6%.

Sitagliptin freebase may be taken in a suitable solvent, to whichphosphoric acid may be added. The contents may be stirred at a highertemperature, such as about 70° C. The contents may be cooled to about30° C. The separated solid may be isolated by conventional techniques,such as decantation, centrifugation, gravity filtration, suctionfiltration, or other techniques known in the art for the recovery ofsolids. The resulting product may be optionally dried. Drying may becarried out in a tray dryer, vacuum oven, air oven, fluidized bed drier,spin flash dryer, flash dryer, and the like. The drying may be carriedout at a temperature of less than about 100° C., or less than about 90°C., or less than about 60° C., or any other suitable temperature atatmospheric pressure or under reduced pressure. The drying can becarried out for any desired time ranging from about 1 to 20 hours orlonger.

In addition to Form A, the present invention includes the sulfuric acid,hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid,oxalic acid, succinic acid, mandelic acid, fumaric acid, and lactic acidsalts of sitagliptin, which salts may be in crystalline form, and whichmay be made by the processes of the present invention.

For example, there is provided crystalline sitagliptin sulfate havingPXRD characteristic peaks at approximately 4.63, 14.06, 14.20, 15.30,17.98, 18.23, 18.79, 19.23, 21.95, 23.23, 26.29 and 26.73±0.2 degrees 2theta. The crystalline sitagliptin sulfate may be characterized by anPXRD pattern substantially as shown in FIG. 4. Crystalline sitagliptinsulfate may also be characterized by a DSC endotherm peak at about 192°C. The crystalline sitagliptin sulfate may be characterized by a DSCthermogram substantially as shown in FIG. 5. The crystalline sitagliptinsulfate may also be characterized by a TGA weight loss of about 0.0029%.The crystalline sitagliptin sulfate may be characterized by a TGA curvesubstantially as shown in FIG. 6.

For example, there is provided crystalline sitagliptin hydrobromidehaving PXRD characteristic peaks at approximately 5.92, 6.81, 13.45,17.53, 21.88, 22.67, 24.39, 25.03 and 26.41±0.2 degrees 2 theta. Thecrystalline sitagliptin hydrobromide may be characterized by an PXRDpattern substantially as shown in FIG. 7. Crystalline sitagliptinhydrobromide may also be characterized by a DSC endotherm peak at about137° C. The crystalline sitagliptin hydrobromide may be characterized bya DSC thermogram substantially as shown in FIG. 8. The crystallinesitagliptin hydrobromide may also be characterized by a TGA weight lossof about 4.178%. The crystalline sitagliptin hydrobromide may becharacterized by a TGA curve substantially as shown by FIG. 9.

For example, there is provided crystalline sitagliptin methane sulfonatehaving PXRD characteristic peaks at approximately 5.25, 6.32, 6.62,11.42, 18.01, 19.14 and 23.91±0.2 degrees 2 theta. The crystallinesitagliptin methane sulfonate may be characterized by an PXRD patternsubstantially as shown in FIG. 10. Crystalline sitagliptin methanesulfonate may also be characterized by a DSC endotherm peak at about131° C. The crystalline sitagliptin methane sulfonate may becharacterized by a DSC thermogram substantially as shown in FIG. 11. Thecrystalline sitagliptin methane sulfonate may also be characterized by aTGA weight loss of about 3.386%. The crystalline sitagliptin methanesulfonate may be characterized by a TGA curve substantially as shown byFIG. 12.

For example, there is provided crystalline sitagliptin acetate havingPXRD characteristic peaks at approximately 6.42, 7.61, 10.25, 12.58,19.51, 19.80, 20.54, 22.89, 25.26 and 25.98±0.2 degrees 2 theta. Thecrystalline sitagliptin acetate may be characterized by an PXRD patternsubstantially as shown in FIG. 13. Crystalline sitagliptin acetate mayalso be characterized by a DSC endotherm peak at about 144° C. Thecrystalline sitagliptin acetate may be characterized by a DSC thermogramsubstantially as shown in FIG. 14. The crystalline sitagliptin acetatemay also be characterized by a TGA weight loss of about 14.16%. Thecrystalline sitagliptin acetate may be characterized by a TGA curvesubstantially as shown by FIG. 15.

For example, there is provided crystalline sitagliptin benzoate havingPXRD characteristic peaks at approximately 7.19, 7.45, 18.11, 18.38,19.35, 20.42, 21.81, 22.61, 24.11, 24.63 and 27.51±0.2 degrees 2 theta.The crystalline sitagliptin benzoate may be characterized by an PXRDpattern substantially as shown in FIG. 16. Crystalline sitagliptinbenzoate may also be characterized by a DSC endotherm peak at about 155°C. The crystalline sitagliptin benzoate may be characterized by a DSCthermogram substantially as shown in FIG. 17. The crystallinesitagliptin benzoate may also be characterized by a TGA weight loss ofabout 0.1163%. The crystalline sitagliptin benzoate may be characterizedby a TGA curve substantially as shown by FIG. 18.

For example, there is provided crystalline sitagliptin oxalate havingPXRD characteristic peaks at approximately 5.92, 11.54, 11.92, 14.00,16.39, 16.64, 19.40, 22.21, 24.00, 28.11 and 28.26±0.2 degrees 2 theta.The crystalline sitagliptin oxalate may be characterized by an PXRDpattern substantially as shown in FIG. 19. Crystalline sitagliptinoxalate may also be characterized by a DSC endotherm peak at about 98°C. The crystalline sitagliptin oxalate may be characterized by a DSCthermogram substantially as shown in FIG. 20. The crystallinesitagliptin oxalate may also be characterized by a TGA weight loss ofabout 6.245%. The crystalline sitagliptin oxalate may be characterizedby a TGA curve substantially as shown by FIG. 21.

For example, there is provided crystalline sitagliptin succinate havingPXRD characteristic peaks at approximately 13.06, 13.50, 15.73, 17.04,17.35, 17.57, 20.15, 24.35, 25.15, 25.76 and 26.35±0.2 degrees 2 theta.The crystalline sitagliptin succinate may be characterized by an PXRDpattern substantially as shown in FIG. 19. Crystalline sitagliptinsuccinate may also be characterized by a DSC endotherm peak at about120° C. The crystalline sitagliptin succinate may be characterized by aDSC thermogram substantially as shown in FIG. 20. The crystallinesitagliptin succinate may also be characterized by a TGA weight loss ofabout 0.8623%. The crystalline sitagliptin succinate may becharacterized by a TGA curve substantially as shown by FIG. 21.

For example, there is provided crystalline sitagliptin mandelate havingPXRD characteristic peaks at approximately 5.45, 6.02, 7.47, 10.60,14.33, 15.88, 17.35, 17.60, 19.02, 21.98, 22.63 and 25.04±0.2 degrees 2theta. The crystalline sitagliptin mandelate may be characterized by anPXRD pattern substantially as shown in FIG. 22. Crystalline sitagliptinmandelate may also be characterized by a DSC endotherm peak at about169° C. The crystalline sitagliptin mandelate may be characterized by aDSC thermogram substantially as shown in FIG. 23. The crystallinesitagliptin mandelate may also be characterized by a TGA weight loss ofabout 0.149%. The crystalline sitagliptin mandelate may be characterizedby a TGA curve substantially as shown by FIG. 24.

For example, there is provided crystalline sitagliptin fumarate havingPXRD characteristic peaks at approximately 6.19, 7.09, 15.93, 16.87,17.12, 19.09, 21.87, 24.15, 25.26, 26.00 and 26.19±0.2 degrees 2 theta.The crystalline sitagliptin fumarate may be characterized by an PXRDpattern substantially as shown in FIG. 25. Crystalline sitagliptinfumarate may also be characterized by a DSC endotherm peak at about 187°C. The crystalline sitagliptin fumarate may be characterized by a DSCthermogram substantially as shown in FIG. 26. The crystallinesitagliptin fumarate may also be characterized by a TGA weight loss ofabout 0.238%. The crystalline sitagliptin fumarate may be characterizedby a TGA curve substantially as shown by FIG. 27.

For example, there is provided crystalline sitagliptin lactate havingPXRD characteristic peaks at approximately 7.91, 10.52, 17.66, 17.92,20.34, 21.59, 23.87, 24.62 and 25.75±0.2 degrees 2 theta. Thecrystalline sitagliptin lactate may be characterized by an PXRD patternsubstantially as shown in FIG. 28. Crystalline sitagliptin lactate mayalso be characterized by a DSC endotherm peak at about 151° C. Thecrystalline sitagliptin lactate may be characterized by a DSC thermogramsubstantially as shown in FIG. 29. The crystalline sitagliptin lactatemay also be characterized by a TGA weight loss of about 0.06007%. Thecrystalline sitagliptin lactate may be characterized by a TGA curvesubstantially as shown by FIG. 30.

The present invention includes processes for the preparation of salts ofsitagliptin, which processes comprise at least one of the steps of:

(a) providing a solution of a salt of sitagliptin in a solvent;

(b) isolating the salt of sitagliptin from the solution of Step (a); and

(c) recovering the crystalline salt of sitagliptin and optionally dryingit.

Step (a) involves providing a solution of a salt of sitagliptin in asolvent

The solution of a salt of sitagliptin may be obtained, for example, bydissolving a salt of sitagliptin of any form in a solvent. It may alsobe obtained by treating a reaction mixture comprising sitagliptin freebase with an acid in a solvent, wherein the acid is sulfuric acid,hydrobromic acid, methanesulfonic acid, acetic acid, benzoic acid,oxalic acid, succinic acid, mandelic acid, fumaric acid lactic acid, ora combination thereof.

Solvents that may be used as in Step (a) include and are not limited toalcohols, such as, for example, methanol, ethanol, isopropanol, andn-butanol; organic acids, such as, for example, acetic acid andpropionic acid; ketones, such as, for example, acetone, methyl isobutylketone, methyl ethyl ketone, and n-butanone; halogenated solvents, suchas, for example, dichloromethane, ethylene dichloride, and chloroform;esters, such as, for example, ethyl acetate, n-propyl acetate, andisopropyl acetate; hydrocarbon solvents, such as, for example, toluene,xylene, n-hexane, n-heptane, and cyclohexane; ethers, such as, forexample, 1,4-dioxane and tetrahydrofuran; aprotic polar solvents, suchas, for example, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO),and dimethylacetamide (DMA); or mixtures thereof.

If Step (a) involves dissolution of a salt of sitagliptin, thedissolution temperature may be less than about 100° C., or less thanabout 90° C., or less than about 80° C., or less than about 60° C., orless than about 50° C., or any other temperature, as long as thestability of the compound is not compromised and a clear solution isobtained.

In the case of salt formation in situ, suitable reaction masstemperature for addition of acid may be less than about 100° C., or lessthan about 90° C., or less than about 80° C., or less than about 60° C.,or less than about 50° C., or any other temperature, as long as thestability of the compound is not compromised and a clear solution isobtained.

Step (b) involves isolating the salt of sitagliptin from the solution ofStep (a).

The salt of sitagliptin may be isolated from the solution of the salt ofsitagliptin by processes known in the art. Various isolation techniquesthat may be used for recovering the salt of sitagliptin include and notlimited to precipitation by cooling, concentration, seeding, and addinganti-solvent; distillation; and evaporation. If desired, the solutionmay be concentrated by conventional methods such as evaporation,distillation before cooling the solution. The exact cooling temperatureand time required for complete crystallization may be readily determinedby a person skilled in the art and will also depend on parameters, suchas concentration and temperature of the solution or slurry. Stirring orother methods, such as shaking, agitation, and the like, that mix thecontents thoroughly may be employed for crystallization to occur.

During isolation of the crystals, the suspension may be maintained for atime sufficient to achieve the complete isolation of the product withdesired yield and quality. Such a time may vary from about 1 to about 48hours or longer.

Step (c) involves recovering the crystalline salt of sitagliptin andoptionally drying it

The crystalline solid may then be recovered from the suspension by usingany of techniques, such as filtration by gravity or by suction,centrifugation, slow evaporation, or any other suitable technique. Thecrystals so isolated may carry a small proportion of occluded motherliquor containing a higher percentage of impurities. If desired, thecrystals may be washed with a solvent to wash out the mother liquorand/or impurities, and the resulting wet crystals may optionally besuction dried.

The wet cake obtained in Step (c) may be optionally dried. Drying may becarried out in a tray dryer, vacuum oven, air oven, fluidized bed drier,spin flash dryer, flash dryer, and the like. The drying may be carriedout at temperature of less than about 200° C., between about 20° C. toabout 80° C., between about 30° C. to about 60° C., or any othersuitable temperature, at atmospheric pressure or under reduced pressure.The drying may be carried out for any desired time until the desiredquality of product is achieved.

The present invention includes pharmaceutical compositions containing atherapeutically effective amount of sitagliptin or a pharmaceuticallyacceptable salt thereof, containing less than about 0.1% of anyindividual impurity, together with one or more pharmaceuticallyacceptable excipients.

Pharmaceutical compositions according to the present invention may beformulated as: solid oral dosage forms including powders, granules,pellets, tablets, and capsules; liquid oral dosage forms includingsyrups, suspensions, dispersions, and emulsions; and injectablepreparations including solutions, dispersions, and freeze driedcompositions. Formulations may be adapted for immediate release, delayedrelease, or modified release of the active ingredient. Immediate releasecompositions may be conventional, dispersible, chewable, mouthdissolving, or flash melt preparations. Modified release compositionsmay comprise hydrophilic and/or hydrophobic, release rate controllingsubstances to form matrix and/or reservoir systems. The pharmaceuticalcompositions may be prepared by direct blending, dry granulation, wetgranulation, extrusion, and/or spheronization. The pharmaceuticalcompositions may be presented as uncoated, film coated, sugar coated,powder coated, enteric coated, or modified release coated.

Compositions of the present invention comprise one or morepharmaceutically acceptable excipients. Pharmaceutically acceptableexcipients that find use in the present invention include and are notlimited to: diluents, such as, for example, starch, pregelatinizedstarch, lactose, powdered cellulose, microcrystalline cellulose,dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar,and the like; binders, such as, for example, acacia, guar gum,tragacanth, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose,hydroxypropyl methylcellulose, pregelatinized starch, and the like;disintegrants, such as, for example, starch, sodium starch glycolate,pregelatinized starch, crospovidone, croscarmellose sodium, colloidalsilicon dioxide, and the like; lubricants, such as, for example, stearicacid, magnesium stearate, zinc stearate, and the like; glidants, suchas, for example, colloidal silicon dioxide and the like; solubility orwetting enhancers, such as, for example, anionic, cationic, or neutralsurfactants; complex forming agents, such as, for example, variousgrades of cyclodextrins and resins; release rate controlling agents,such as, for example, hydroxypropyl cellulose, hydroxymethyl cellulose,hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, variousgrades of methyl methacrylates, waxes, and the like. Otherpharmaceutically acceptable excipients that are of use include but arenot limited to film formers, plasticizers, colorants, flavoring agents,sweeteners, viscosity enhancers, preservatives, antioxidants, and thelike.

Certain specific aspects and embodiments of the present application willbe explained in greater detail with reference to the following examples,which are provided by way of illustration only and should not beconstrued as limiting the scope of the application in any manner.

PXRD data reported herein was obtained using Cu Ka radiation, having thewavelength 1.5418 Å and were obtained using a Bruker AXS D8 AdvancePowder X-ray Diffractometer.

DSC analysis was carried out in a DSC Q1000 instrument from TAInstruments with a ramp of 10° C./minute with a modulation time of 60seconds and a modulation temperature of ±1° C. The starting temperaturewas 0° C. and ending temperature was 200° C.

TGA analysis was carried out in a TGA Q500 instrument with a ramp 10°C./minute up to 250° C.

EXAMPLES Reference Example Preparation of3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinehydrochloride of Formula X Step A: Preparation ofN′-(2-chloroacetyl)-trifluoroacetohydrazide

Hydrazine hydrate (15 g, 35 wt %) is mixed acetonitrile (22.5 mL) andcooled to about 10° C. Ethyl trifluoroacetate (23.3 g) is added over 1hour. The resulting solution is warmed to 20° C. and stirred for about 1hour. The solution is cooled to 0-2° C. 50 wt % aqueous NaOH (7.88 g)and chloroacetyl chloride (22.2 g) are added to the reaction solutionsimultaneously over 2 hours. The reaction mixture is warmed to 15-18° C.and stirred for about 5 hours. Solvent is distilled off under vacuum atabout 30° C. Water (50 mL) and ethyl acetate (100 mL) are added to theobtained crude. The organic and aqueous layers are separated and aqueouslayer is washed with ethyl acetate (2×50 mL). The organic layers arecombined and washed with water (2×50 mL) followed by washing with 15%sodium chloride solution (2×50 mL). The combined organic layer is driedover sodium sulfate. The solvent is completely distilled off undervacuum to afford the title compound. (Yield: 98.3%)

Step B: Preparation of 5-trifluoromethyl-2-chloromethyl-1,3,4-oxadiazole

N′-(2-chloroacetyl)-trifluoroacetohydrazide (60 g) and acetonitrile (120mL) are charged into a round-bottom flask and cooled to about 0° C.Phosphorus oxychloride (27.1 g) is added to the solution for about 15minutes. The reaction mixture is heated to about 80° C. and stirred forabout 28 hours. In a separate vessel, isopropyl acetate (180 mL) andwater (180 mL) are mixed and cooled to 0° C. The reaction slurry isadded to this solution slowly. The organic layer is separated and washedwith 5% sodium bicarbonate solution (180 mL) and finally with 20% sodiumchloride solution (180 mL). The organic layer is dried over sodiumsulfate. The solvent is completely distilled off under vacuum to affordthe title compound. (Yield: 82.2%)

Step C: Preparation ofN′-((Z)-piperazin-2-ylidene)-trifluoroacetohydrazide

The solution of ethylene diamine (89 g) in methanol (305 mL) is stirredand cooled to −20° C. over about 45 minutes.5-(trifluoromethyl)-2-(chloromethyl)-1,3,4-oxadiazole (79 g) is addedslowly to the solution over 90 minutes at −20° C. The resulting slurryis stirred for about 90 minutes at −20° C. Ethanol (482 mL) is added andthe slurry is warmed to −5° C. After stirring for about 2 hours at −5°C., the solid is filtered, washed with ethanol (79 mL) and dried atabout 55° C. to afford the title compound. (Yield: 46.8%)

Step D: Preparation of3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinehydrochloride (Formula X)

A suspension of N′-((Z)-piperazin-2-ylidene)-trifluoroacetohydrazide (41g) in methanol (170 mL) is stirred and heated to about 55° C. Hydrogenchloride (21 mL) is added to the reaction mixture and stirred for about2 hours. The solution is cooled to 20° C. and methyl tert-butyl ether(423 mL) is added to it. The solution is further cooled to 0° C. andstirred for about 1 hour. The solid is filtered, washed with mixture ofethanol and methyl tert-butyl ether (82 mL) and dried at about 45° C. toafford the title compound. (Yield: 90.7%)

Example 1 Preparation of5-(1-hydroxy-2-(2,4,5-trifluorophenyl)-ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(Formula XI)

2,4,5-trifluorophenylacetic acid (30 g), tetrahydrofuran (360 mL),1,1-carbonyl diimidazole (25.5 g) at about 50° C., and meldrums acid(22.7 g) are combined. The mixture is stirred for about five hours atthe same temperature. The reaction mass is then cooled to about 30° C.Isopropyl acetate (180 mL) and water (180 mL) are added and stirred forabout 30 minutes. The reaction mass is cooled to about 0° C. and pH isadjusted to about 2.4 using 36% aqueous hydrochloric acid. The organiclayer is separated, washed with 0.1 N aqueous hydrochloric acid anddistilled off completely. To the residue obtained, n-heptane (140 mL)and isopropyl acetate (70 mL) are charged at about 30° C. and stirred atabout 0° C. for about 90 minutes. The separated solid is filtered andwashed with a mixture of n-heptane (20 mL) and isopropyl acetate (10mL). The wet cake is dried at about 50° C. for about 4 hours to affordthe title compound. (Yield: 60.1%; purity by HPLC: 98.0%)

Example 2 Preparation of7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(Formula VI)

A mixture of5-(1-hydroxy-2-(2,4,5-trifluorophenyl)-ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione(10 g),3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinehydrochloride (7.2 g), diisopropyl ethylamine (4.5 g), and isopropylacetate (100 mL) are heated to about 85° C. and stirred for about 4hours. The reaction mass is then cooled to about 30° C. and quenchedwith water (90 mL). The organic layer is separated, washed with 5%sodium chloride solution (3×50 mL) and distilled off completely undervacuum to afford 12 g of the title compound. (Yield: 93.3%; purity byHPLC: 95.7%)

Example 3 Preparation of7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(Formula V)

A mixture of7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(22.1 g), ammonium acetate (25 g), methanol (220 mL), and aqueousammonia (22 mL) are heated to about 55° C. and stirred for about 6hours. The reaction mass is then cooled to 30° C. and the undissolvedparticles are filtered off. The filterate is distilled off completelyunder vacuum. To the residue, ethanol (25 mL) is charged and the mixtureis stirred at about 30° C. for about 30 minutes. The solid is filtered,washed with ethanol (5 mL), and dried to afford the title compound.(Yield: 75%; purity by HPLC: 96.7%)

Example 4 Preparation of7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(Formula IV)

A mixture of methanol (135 ml),7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(13.5 gm), sodium cyano borohydride (2.5 g), and methanolic hydrogenchloride (35 mL) at about 4.5 pH is stirred for about 5 hours at about30° C. The solvent is distilled off completely and water (50 mL) isadded to the residue. The extraction is carried out with ethylacetate(150 mL). The obtained organic layer is distilled off completely toafford the title compound. (Yield: 99.9%; purity by HPLC: 92.25%)

Example 5 Preparation of Sitagliptin di-p-tolyl-L-tartarate salt

A mixture of methanol (390 mL), water (80 mL),7-(1-oxo-3-amino-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(13 g), and di-p-tolyl-L-tartaric acid (13 g) is stirred for about 24hours. The separated solid is filtered off, washed with ethanol (15 mL)and dried at about 45° C. to afford the title compound. (Yield: 66.3%;purity by HPLC: 99.93%)

Example 6 Preparation of Sitagliptin phosphate monohydrate (Formula I)

10% sodium hydroxide solution (1 mL) is added to a mixture ofethylacetate (10 mL), water (5 mL), sitagliptin di-p-tolyl-L-tartarate(0.4 g) under stirring at about 5° C. The mixture is stirred for about30 minutes. The layers are separated and the aqueous layer is extractedwith ethyl acetate (10 mL). The combined organic layer is distilled offcompletely to afford 0.2 gm of sitagliptin freebase.

The sitagliptin freebase is dissolved in a mixture of isopropyl alcohol(5 mL) and water (0.2 mL), to which 85% phosphoric acid (0.056 g) isadded. The contents are heated to about 70° C. for about 30 minutes,then cooled to about 30° C., and stirred for about 15 hours. Theseparated solid is filtered, washed with isopropyl alcohol (1 mL), anddried at about 50° C. for about 3 hours to afford the title compound.(Yield: 68%; purity by HPLC: 99.87%; SOR: −20.7° C. (c=1% in water))

Example 7 Preparation of(Z)-7-(1-oxo-3((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(Formula VIII)

A mixture of isopropanol (10 mL),7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(2 g), and R-1-phenylethanamine are heated to about 40° C. Acetic acid(0.15 mL) is added and stirred for about 5 hours. The solvent isdistilled off completely to afford the title compound. (Yield: 99.7%;m/z: 510 (m+1))

Example 8 Preparation of7-(1-oxo-3((R)-((R)-1-phenylethylamino))-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(Formula IX)

Tetrahydrofuran (80 ml), methanol (20 ml),(Z)-7-(1-oxo-3((R)-1-phenylethylamino)-4-(2,4,5-trifluorophenyl)-but-2-enyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(8 g), and platinum oxide (1.0 g) are charged in an autoclave vessel andthe contents are heated to about 40° C. H₂ gas pressure of about 12-14kg/cm² is applied and maintained for about 10 hours at the sametemperature. The reaction mass is then cooled to about 30° C. and thenthe catalyst is filtered off. The filterate is distilled off completelyunder vacuum to afford 8.2 gm of the title compound.

Example 9 Preparation of Sitagliptin (Formula II)

Tetrahydrofuran (10 mL), methanol (10 mL),7-(1-oxo-3((R)-((R)-1-phenylethylamino))-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(2 g), formic acid (2 mL), 20% palladium hydroxide carbon (0.5 g), andwater (2 mL) are charged in a round-bottom flask and the contents areheated to about 60° C. for about 6 hours. The reaction mass is thencooled to about 30° C. and the catalyst is filtered. The filtrate isdistilled off completely under vacuum. Water (10 mL) and ethyl acetate(20 mL) are charged to the residue and it is cooled to about 0° C.Phosphoric acid (0.4 g) is added to the reaction mass and the layers areseparated. Aqueous layer is cooled to about 0° C. and 5% sodiumhydroxide is added till pH of the mass is attained to about 12.0. Themass is then extracted with ethyl acetate (20 mL) and the ethyl acetatelayer is distilled off completely to afford the title compound. (Yield:79.4%)

Example 10 Preparation of Sitagliptin phosphate monohydrate (Formula I)

7-[(3R)-3-Amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazineof Formula II (0.4 g), isopropanol (5 mL), water (0.4 mL), andphosphoric acid (0.11 g) are charged and heated to about 70° C. forabout 3 hours. The reaction mass is then cooled to about 30° C. andstirred for about 10 hours. The separated solid is filtered and dried atabout 45° C. under vacuum for about 4 hours to afford the titlecompound. (Yield: 68%; purity by HPLC: 96.67%; purity by chiral HPLC:99.19%; m/z: 408(m+1); SOR: −21° C. (c=1% in water))

Example 11 Preparation of Sitagliptin (Formula II)

10% sodium hydroxide solution (10 mL) is added to a mixture of7-(1-oxo-3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazinedi-p-tolyl-L-tartarate salt (8.5 g), and ethyl acetate (30 mL) at about10° C. The mixture is stirred at the same temperature until clear. Thelayers are then separated and the organic layer is distilled completely.Isopropanol (5 mL) is charged and stirred until the solution is clear.To the solution, n-heptane (25 mL) is charged and stirred for about 9hours. The solid is filtered, washed with n-heptane (5 mL), and driedunder reduced pressure to afford the title compound. (Yield: 99.5%)

Example 12 Preparation of Sitagliptin phosphate monohydrate (Formula I)

A mixture of7-(1-oxo-3-((R)-amino)-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine(2 gm), water (2 mL), isopropanol (4 mL), and 85% phosphoric acid (0.567g) is heated to about 75° C. and stirred until the mixture is clear. Themixture is then cooled to about 68° C. and stirred for about 2 hours. Itis further cooled to about 4° C. and stirred overnight. Isopropanol (14mL) is charged and stirred for about one hour. The solid is filtered andwashed with mixture of isopropanol (4.5 mL) and water (0.5 mL) to affordthe title compound. (Yield: 93.38%; purity by HPLC: 99.96%)

Example 13 Preparation of Anhydrous Crystalline Sitagliptin DihydrogenPhosphate (Form A)

10% sodium hydroxide solution (15 mL) is added to a mixture of ethylacetate (25 mL), water (20 mL), and sitagliptin di-p-tolyl-tartaratesalt (8.0 g) under stirring at about 5° C. The mixture is stirred forabout 30 minutes. The layers are separated and the aqueous layer isextracted with ethyl acetate (50 mL). The combined organic layer isdistilled off completely to afford 4.1 g of sitagliptin freebase.

The sitagliptin freebase is dissolved in a mixture of isopropanol (80mL) and water (4.0 mL). 85% phosphoric acid (1.13 g) is added. Thecontents are heated to about 70° C. for about 30 minutes, then cooled toabout 30° C., and stirred for about 15 hours. The separated solid isfiltered, washed with isopropanol (1 mL), and dried at about 50° C. forabout 3 hours to afford the title compound. (Yield: 85.6%; purity byHPLC: 99.96%)

Example 14 Preparation of Sitagliptin Sulfate

Sitagliptin (5 g) and isopropanol (75 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about15 minutes to obtain a clear dissolution. Sulfuric acid (1.2 g) is addedand the reaction mixture is refluxed for about 1 hour. The reactionmixture is cooled to about 30° C. and stirred for about 22 hours. Theseparated solid is filtered, washed with isopropanol (5 mL), and driedunder reduced pressure at about 40° C. for about 1.5 hours to afford thetitle compound. (Yield: 6.0 g; MC: 0.84% w/w; HPLC purity: 99.98%)

Example 15 Preparation of Sitagliptin Hydrobromide

Sitagliptin (5 g) and isopropanol (75 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about30 minutes to obtain a clear dissolution. Hydrobromic acid (2.1 g) isadded and the reaction mixture is refluxed for about 1.5 hours. Thereaction mixture is cooled to about 30° C. and stirred for about 22hours. The separated solid is filtered, washed with isopropanol (5 mL),and dried under reduced pressure at about 35° C. for about 1.25 hours toafford the title compound. (Yield: 4.0 g; MC: 2.40% w/w; HPLC purity:99.70%)

Example 16 Preparation of Sitagliptin Methane Sulfonate

Sitagliptin (5 g) and isopropanol (50 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about20 minutes to obtain a clear dissolution. Methane sulfonic acid (1.11 g)is added and the reaction mixture is refluxed for about 1.5 hours. Thereaction mixture is cooled to about 30° C. and stirred for about 16hours. The separated solid is filtered, washed with isopropanol (5 mL),and dried under reduced pressure at about 45° C. for about 2.5 hours toafford the title compound. (Yield: 6.0 g; MC: 0.97% w/w; HPLC purity:99.92%)

Example 17 Preparation of Sitagliptin Acetate

Sitagliptin (5 g) and isopropanol (75 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about20 minutes to obtain a clear dissolution. Acetic acid (0.73 g) is addedand the reaction mixture is refluxed for about 1.5 hours. The reactionmixture is cooled to about 30° C. and stirred for about 8.5 hours. Theseparated solid is filtered, washed with isopropanol (5 mL), and driedunder reduced pressure at about 30° C. for about 3.5 hours to afford thetitle compound. (Yield: 5.6 g; MC: 0.79% w/w; HPLC purity: 99.81%)

Example 18 Preparation of Sitagliptin Benzoate

Sitagliptin (5 g) and isopropanol (75 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about20 minutes to obtain a clear dissolution. Benzoic acid (1.49 g) is addedand the reaction mixture is refluxed for about 1.5 hours. The reactionmixture is cooled to about 30° C. and stirred for about 21.5 hours. Theseparated solid is filtered, washed with isopropanol (5 mL), and driedunder reduced pressure at about 40° C. for about 1.5 hours to afford thetitle compound. (Yield: 5.9 g; MC: 0.80% w/w; HPLC purity: 99.82%)

Example 19 Preparation of Sitagliptin Oxalate

Sitagliptin (5 g) and isopropanol (75 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about30 minutes to obtain a clear dissolution. Oxalic acid (1.54 g) dissolvedin water (5 mL) is added and the reaction mixture is refluxed for about1 hour. The reaction mixture is cooled to about 30° C. and stirred forabout 22 hours. The separated solid is filtered, washed with isopropanol(5 mL), and dried under reduced pressure at about 40° C. for about 2.5hours to afford the title compound. (Yield: 5.8 g; MC: 6.54% w/w; HPLCpurity: 99.95%)

Example 20 Preparation of Sitagliptin Succinate

Sitagliptin (5 g) and isopropanol (50 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about30 minutes to obtain a clear dissolution. Succinic acid (1.44 g) isadded and the reaction mixture is refluxed for about 1.5 hours. Thereaction mixture is cooled to about 30° C. and stirred for about 23hours. The separated solid is filtered, washed with isopropanol (5 mL),and dried under reduced pressure at about 50° C. for about 3 hours toafford the title compound. (Yield: 4.0 g; MC: 1.79% w/w; HPLC purity:99.72%)

Example 21 Preparation of Sitagliptin Mandelate

Sitagliptin (4 g) and isopropanol (60 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about30 minutes to obtain a clear dissolution. Mandelic acid (1.49 g) isadded and the reaction mixture is refluxed for about 1.5 hours. Thereaction mixture is cooled to about 30° C. and stirred for about 21.5hours. The separated solid is filtered, washed with isopropanol (4 mL),and dried under reduced pressure at about 45° C. for about 2 hours toafford the title compound. (Yield: 4.4 g; MC: 0.51% w/w; HPLC purity:99.56%)

Example 22 Preparation of Sitagliptin Fumarate

Sitagliptin (4 g) and isopropanol (60 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about30 minutes to obtain a clear dissolution. Fumaric acid (1.14 g) is addedand the reaction mixture is refluxed for about 2 hours. The reactionmixture is cooled to about 30° C. and stirred for about 21 hours. Theseparated solid is filtered, washed with isopropanol (4 mL), and driedunder reduced pressure at about 45° C. for about 2 hours to afford thetitle compound. (Yield: 4.0 g; MC: 1.05% w/w; HPLC purity: 99.47%)

Example 23 Preparation of Sitagliptin Lactate

Sitagliptin (5 g) and isopropanol (75 mL) are charged into around-bottom flask and the mixture is heated to about 80° C. for about20 minutes to obtain a clear dissolution. Lactic acid (1.10 g) is addedand the reaction mixture is refluxed for about 1.5 hours. The reactionmixture is cooled to about 30° C. and stirred for about 8.5 hours. Theseparated solid is filtered, washed with isopropanol (5 mL), and driedunder reduced pressure at about 45° C. for about 2 hours to afford thetitle compound. (Yield: 4.0 g; MC: 0.62% w/w; HPLC purity: 99.75%)

The invention claimed is:
 1. A compound of Formula IX or apharmaceutically acceptable salt thereof,

wherein R is C₁-C₄ alkyl.
 2. The compound of claim 1 which is,

or a pharmaceutically acceptable salt thereof.
 3. A process for thepreparation of sitagliptin of the formula II

or a pharmaceutically acceptable salt thereof, comprising a) thedeprotection of a compound of Formula IX or a pharmaceuticallyacceptable salt thereof,

 wherein R is C₁-C₄ alkyl, and b) optionally, treating a compound ofFormula II with a pharmaceutically acceptable acid to afford apharmaceutically acceptable salt of the compound of Formula II.
 4. Theprocess of claim 3, wherein deprotection of the compound of Formula IXis done in the presence of platinum oxide.
 5. The process of claim 3,wherein said pharmaceutically acceptable acid is selected fromhydrochloric acid and phosphoric acid.